Interleukin 4 receptor on human lung cancer: a molecular target for cytotoxin therapy.

Abstract

Previous studies have demonstrated that human lung tumor cell lines express interleukin 4 (IL-4) receptors, and IL-4 can mediate modest to moderate antiproliferative activity in vitro and in vivo in animal models of human lung tumors. On the basis of these studies, IL-4 was tested in clinical trials; however, it showed little antitumor activity in lung cancer patients. In the present study, we examined the expression of IL-4 receptors (IL-4Rs) in lung tumor samples and normal lung tissues and tested whether an IL-4R targeted agent will have better antitumor activity in vitro and in vivo compared with IL-4. IL-4R expression was tested by immunohistochemistry in 54 lung tumor samples and normal lung tissues in a tissue array, by reverse-transcription PCR and Northern blot analyses in lung tumor cell lines. Cytotoxic activity of IL-4 cytotoxin [IL-4(38-37)-PE38KDEL], composed of a circular permuted IL-4 and a mutated form of Pseudomonas exotoxin (PE38KDEL) was tested by protein synthesis inhibition and clonogenic assays in seven lung tumor cell lines. Antitumor activity of IL-4 cytotoxin was tested in vitro and in immunodeficient animal models of human lung tumors. We observed that IL-4Rs are expressed at higher levels in situ in lung tumor samples compared with normal lung tissues and IL-4 cytotoxin is highly and specifically cytotoxic to lung tumor cell lines in vitro. Intratumoral and i.p. administration of IL-4 cytotoxin to immunodeficient mice with s.c. established human lung H358 non-small cell lung cancer tumors mediated considerable antitumor activity in a dose-dependent manner with the higher dose producing durable complete responses. On the other hand, H460 non-small cell lung cancer tumors expressing low levels of IL-4R did not respond to IL-4 cytotoxin therapy. Because IL-4 cytotoxin mediates its antitumor activity through IL-4R, and a variety of lung tumors expressed high levels of IL-4R, we propose testing the safety of this agent in patients with lung cancer.

• Authors: Mariko Kawakami, Koji Kawakami, Vitaly A Stepensky, Richard A Maki, Howard Robin, Wayne Muller, Syed R Husain, Raj K Puri
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 8 Issue 11 Pg. 3503-11 (Nov 2002) ISSN: 1078-0432 [Print] United States
• PMID: 12429641 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cytotoxins
• Exotoxins
• Protein Synthesis Inhibitors
• RNA, Messenger
• Receptors, Interleukin-4
• Recombinant Proteins
• Interleukin-4

Topics

• Animals
• Blotting, Northern
• Body Weight
• Carcinoma, Non-Small-Cell Lung (pathology)
• Cytotoxins (pharmacology)
• Dose-Response Relationship, Drug
• Exotoxins (pharmacology)
• Humans
• Immunohistochemistry
• Interleukin-4 (metabolism)
• Kinetics
• Lung Neoplasms (metabolism, pathology)
• Male
• Mice
• Mice, Nude
• Mutation
• Neoplasm Transplantation
• Polymerase Chain Reaction
• Protein Binding
• Protein Synthesis Inhibitors (pharmacology)
• Pseudomonas (metabolism)
• RNA, Messenger (metabolism)
• Radioligand Assay
• Receptors, Interleukin-4 (metabolism)
• Recombinant Proteins (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• Tumor Cells, Cultured